Activating mutations of KRAS and losses of INK4a/ARF are thought to occur at the early stages of pancreatic adenocarcinoma pathogenesis while losses of p53 and SMAD4 are associated with the emergence of more advanced lesions. An important challenge is to understand how these genetic lesions contribute to the cancer biology and to generate preclinical models of this disease. The construction of a refined mouse model of pancreatic adenocarcinoma, a long-sought objective in the field, would not only bridge this genotype-phenotype chasm but also help to identify other cooperating lesions and assess whether such genetic lesions are good cancer drug targets. I propose to develop mouse models that will 1) assess the cooperative roles of activated Kras and Ink4a/Arf deficiency in tumor initiation and progression, 2) assign a role for activated Kras in the maintenance of pancreatic adenocarcinoma and 3) serve as a system for preclinical trials and cancer gene discovery. My gene discovery efforts will apply array comparative genomic hybridization (aCGH). I expect that the implementation of aCGH in conjunction with these mouse model systems should lead to significant insights into the genes and processes driving pancreatic cancer genesis/progression. aCGH analysis of human tumors will allow rapid prioritization of candidate loci for future cancer gene cloning efforts. A second aspect of these studies will employ expression of an inducible mutant Kras allele in the pancreatic epithelium. The inducible Kras allele should enable the study of the role of this oncogene in fully formed tumors, specifically with respect to tumor cell proliferation and survival and tumor-stroma interactions. In future studies, I plan to exploit the inducible system to identify the Kras-dependent transcriptome at multiple stages of tumorigenesis. This model will provide a genetic system in which to identify keystone elements of the Kras pathway that can serve as candidates for drug development. Career Development. For a final year, I wish to remain in this mentored environment where I have access to resources necessary for the full realization of my program that will form the basis of my independent career. Dr. DePinho will continue to provide guidance for improving of my skills in executing increased project management responsibilities. The Harvard community offers extensive relevant expertise and collaborative opportunities. I plan within the upcoming year to prepare an R01 application proposing the elaboration of the studies described in this K01 grant. As I transition towards an independent faculty position, I will seek a research environment with a strong basic science focus complemented by close collaboration with physician-scientists in order to translate discoveries into relevant advances for treating the human disease. An important component of my program will be my continued participation in a multidisciplinary consortium of pancreatic cancer researchers currently in the process of addressing a series of programmatic initiatives.